The proposal is designed to obtain funding for career enhancement for Dr. Irina Korichneva, an Assistant Professor of Medicine at UMDNJ - Robert Wood Johnson Medical School. Candidate has a solid background in cell biology and biochemistry with the emphasis on signal transduction. Her recent research focus is zinc homeostasis and redox signaling. Cardiovascular diseases are multi-factorial conditions that remain the leading cause of death worldwide. Current therapies by classical pharmacological means face limitations and only delay progression of the disease. Cardiac remodeling during heart failure involves myocardial cell hypertrophy and apoptosis followed by fibrosis. It is clear that instead of treating symptoms, targeting the pathophysiology, i.e. cardiomyocyte degeneration, cardiac regeneration represents a better, although challenging, alternative. Cardiopoietic programming is a new therapeutic strategy to regenerate dysfunctional myocardium. Resident cardiac stem cells have been found in adult myocardium and they were capable to differentiate into multiple cell types present in the heart, including cardiac muscle cells, indicating that the heart is not a terminally differentiated organ. These new findings have stimulated optimism that the use of an allogeneic source for expansion in vitro of cardiac stem cells will allow possibly avoiding associated teratoma formation. Improved efficiency of stem cell therapy and preparation of clinical grade stem cells depend on understanding of the molecular mechanisms guiding the proliferation of progenitors and development of cardiac myocytes. Developing outstanding expertise in stem cell biology and applying this to cardiac stem cell culture in particular has been PI's driving scientific passion for the last several years. She is currently finishing her major NIH funded project and is now working on the renewal of her RO1 grant. Thus, the timing of an application for the career enhancement award is highly appropriate. The award will be particularly valuable to the PI Institution, as they are presently founding a Cardiovascular Institute on the campus. The Cardiovascular Institute will share the building with the Stem Cell Institute of NJ thus creating an outstanding and possibly unique interactive and productive environment in the area of cardiac stem cell research. The preliminary data from the PI's laboratory shows that labile zinc concentrations change with embryonic development and with differentiation of embryonic bodies (EBs). These changes correlate with alterations of ZnT5 zinc transporter expression. The goal of this proposal is learn handling of cardiac stem cells and to characterize the role of zinc homeostasis and zinc transporter ZnT5 in their proliferation and survival. The main hypothesis is that zinc homeostasis regulates proliferative potential and survival of CSCs. These aims will be addressed by biochemical, molecular biology, and fluorescent imaging approaches. All the transfection constructs have been prepared and the assays are being successfully used in the PI's laboratory. In addition, training in human CSC maintenance is planned in the laboratory of Dr. Anversa at Harvard University. T The data obtained will be used to design the protocol for scaling up the production of CSCs for clinical use. PUBLIC HEALTH RELEVANCE: Cardiopoietic programming is a new therapeutic strategy to regenerate dysfunctional myocardium. Stem cells have attracted a great attention of clinical cardiologists. Cardiac-derived stem cells maintain potency to develop to cardiac lineage in culture while they can be expanded without limits for use in regenerative medicine. Cardiovascular diseases face limitations in treatments by classical pharmacological means. Cardiomyocyte degeneration represents a better although challenging alternative.